Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes

Peter Popp Wibroe, Aaron C. Anselmo, Per H. Nilsson, Apoorva Sarode, Vivek Gupta, Rudolf Urbanics, Janos Szebeni, Alan Christy Hunter, Samir Mitragotri, Tom Eirik Mollnes, Seyed Moein Moghimi

Research output: Contribution to journalArticlepeer-review

149 Scopus citations


Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration.

Original languageEnglish (US)
Pages (from-to)589-594
Number of pages6
JournalNature Nanotechnology
Issue number6
StatePublished - Jun 6 2017

ASJC Scopus subject areas

  • Bioengineering
  • Atomic and Molecular Physics, and Optics
  • Biomedical Engineering
  • Materials Science(all)
  • Condensed Matter Physics
  • Electrical and Electronic Engineering


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